Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy

Contains fulltext : 202651.pdf (publisher's version ) (Open Access)OBJECTIVE: To assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD). METHODS: In this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups. RESULTS: Twenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2-3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8-9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%). CONCLUSIONS: Patients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients

Review of the Diagnosis and Treatment of Periodic Paralysis

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.Functional Genomics of Muscle, Nerve and Brain Disorder

Characterizing the face in facioscapulohumeral muscular dystrophy

Contains fulltext : 232742.pdf (Publisher’s version ) (Open Access)OBJECTIVE: To evaluate facial weakness in patients with FSHD to better define clinical signs, and pilot a facial weakness severity score. METHODS: 87 FSHD patients and 55 controls were video recorded while performing seven facial tasks. The videos were assessed by three independent examiners to compile an overview of signs of facial weakness. Next, videos were semi-quantitatively assessed using a newly developed 4-point facial weakness score (FWS). This score was evaluated and correlated to other FSHD disease characteristics. RESULTS: Patients had lower scores on the total FWS than controls (mean score 43 ± 28, range 4-118, vs 14 ± 9, range 0-35, p < 0.001) and on all seven individual facial tasks (all p < 0.001). 54% of patients had FWS scores outside the range of controls. Patients had more asymmetry between the left and right side of the face than controls. About 10% of the patients had very mild facial weakness. These were mostly males (89%) with longer D4Z4 repeat sizes of 7-9 units. More severe facial weakness correlated to more severe overall disease severity and shorter D4Z4 repeat size, but not to disease duration. Interobserver agreement for the FWS between three raters was low with a Fleiss Kappa of 0.437. CONCLUSION: This study provides an overview of the clinical spectrum of facial weakness and its relation to other disease characteristics. The 4-point scale we introduced to grade the severity of facial weakness enables correlation of facial weakness to disease characteristics, but is not suited as clinical outcome measure for longitudinal studies

MUSCLE PATHOLOGY GRADE FOR FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY BIOPSIES

Functional Genomics of Muscle, Nerve and Brain Disorder

Effects of weakness of orofacial muscles on swallowing and communication in FSHD

OBJECTIVE: This study explores the use of quantitative data on strength and fatigability of orofacial muscles in patients with facioscapulohumeral muscular dystrophy (FSHD) and assesses the frequency of swallowing and communication difficulties and their relationship to orofacial muscle involvement. METHODS: We included 43 patients with FSHD and 35 healthy controls and used the Iowa Oral Performance Instrument (IOPI) to obtain quantitative measurements of strength and endurance of lip compression, cheek (buccodental) compression, and tongue elevation. For the assessment of swallowing and communication difficulties, we used the dysphagia-specific quality of life (SWAL-QOL) and Communicative Participation Item Bank questionnaires. RESULTS: Cheek compression strength was reduced in patients with FSHD compared to healthy controls. Dysphagia and difficulty with verbal communication were reported by 25% and 35% of patients, respectively, and correlated to cheek compression strength and endurance and to anterior tongue elevation endurance. Prolonged cheek compression or anterior tongue elevation endurance (decreased fatigability) made swallowing or speech problems less likely to occur. CONCLUSION: Cheek compression strength is the most sensitive IOPI measure for orofacial weakness in FSHD. Orofacial weakness contributes to dysphagia and speech difficulties in FSHD, which are both common, though generally mild. Higher endurance of orofacial muscles was associated with a lower chance of dysphagia or speech problems. More research is required for further refinement of the pattern of facial muscle involvement in FSHD and to provide new insights for improvement of speech and language therapy

Milder phenotype in facioscapulohumeral dystrophy with 7-10 residual D4Z4 repeats

Functional Genomics of Muscle, Nerve and Brain Disorder

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

Contains fulltext : 154813.pdf (publisher's version ) (Open Access)BACKGROUND: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. METHODS/DESIGN: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. DISCUSSION: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02045667

Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1-year follow-up study

Item does not contain fulltextINTRODUCTION: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD). METHODS: Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year. RESULTS: There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning. DISCUSSION: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018

Elevated plasma complement components in facioscapulohumeral dystrophy

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to several therapeutic approaches entering clinical trials and an increased need to develop biomarkers of disease activity and progression. Multiple prior studies have shown early elevation of RNAs encoding components of the complement pathways and relatively widespread activated complement complexes by immunodetection in FSHD muscle. The current study tested plasma from two independent cohorts of FSHD and control subjects and found elevated complement components in both FSHD cohorts. Combining subjects from both cohorts identified complement factors that best distinguished FSHD and controls. Within the FSHD group, a subset of subjects showed elevation in multiple complement components. Together these findings suggest the need for future studies to determine whether measurements of complement activation can be used as a non-invasive measurement of FSHD disease activity, progression and/or response to therapies. In addition, with the ongoing expansion of complement therapeutic approaches, consideration for precision-based targeting of this pathway is appropriate.Functional Genomics of Muscle, Nerve and Brain Disorder